Diclofenac is a well-known non-steroidal anti-inflammatory drug (“NSAID”) used in acute and chronic pain in both parenteral and oral dosage forms. Oral dosages range from 100-200 mg/day, while parenteral dosages range from 75-150 mg/day (1-2 mg/kg/day) by either infusion or intermittent (divided) doses. Toxicity of oral and parenteral forms are well known, with gastro-intestinal, hemorrhagic, renal, hepatic, cardiovascular and allergic (anaphylactic and severe dermal allergy) adverse events being most significant.
Parenteral use of diclofenac has been limited due to limited solubility, such that parenteral preparations have had to include non-polar solvents in order to achieve concentrations (75 mg/3 ml) which would allow intra-muscular (IM) administration of the desired dose. This solubility has limited the parenteral use to IM use and/or slow intravenous (IV) administration of diluted (100-500 ml diluent) product.
U.S. Pat. No. 5,679,660 and co-pending application Ser. No. 10/999,155, filed Nov. 30, 2004, published as U.S. 2005/0238674 A1 on Oct. 27, 2005, both of which are incorporated by reference, disclose novel formulations of diclofenac with hydroxypropyl-beta-cyclodextrin, which allows a more concentrated preparation and thus rapid intravenous administration. The data show that the more concentrated the diclofenac/beta-cyclodextrin formulation, the faster onset of action over current products.
Other than ease of administration and more rapid onset of action, consequent on the improvements in the pharmaceutical formulation, no other advantages were observed. The present invention arises, in part, from the surprising discovery that formulating a non-steroidal anti-inflammatory drug with beta-cyclodextrin not only improves solubility and stability of the drug, it also increases efficacy.